The brain can oxidize glucose and ketone bodies when they are available in the blood. Our objectives are: (1) to evaluate the cerebral control mechanisms which modulate the relative utilization of these substrates; (2) to define associated perturbations in cerebral metabolites; and (3) to characterize the intracellular metabolic fate of ketone bodies after they enter the brain. Several of our speculations are predicated on the fact that ketone bodies are oxidized exclusively within the mitochondria, wherease glucose is metabolized by cytoplasmic and by mitochondrial mechanisms. We propose that ketone body utilization effects stabilization of the neuronal membrane resulting in an elevation of the convulsive threshold. Biochemical studies designed to validate this proposal will be carried out on suckling rats and on adult rats made ketotic by intravenous infusions of beta-hydroxybutyrate, by starvation, and by high-fat-feedings. Our methods will include radioisotope tracer studies using (U-C14)glucose to evaluate the quantitative significance of the apparent inhibition of glucose oxidation associated with ketosis. (3-C14)beta-hydroxybutyrate will be injected into suckling rats between birth and 15 days of age to evaluate its role as a precursor for brain cholesterol during early development. We will attempt to measure guanine and adenine nucleotides, cyclic nucleotides, and acetylcholine in ketotic rats resistant to electroconvulsive shock. In vitro studies will be performed on cerebral slices and on isolated synaptosomes to evaluate the oxidation of ketone bodies under varying conditions. The relative protection afforded the adult rat by systemic ketosis against several chemical convulsants will be determined and correlated with biochemical observations. A collaborative study will be carried out to correlate electrophysiological and biochemical observations in the ketotic cat. Initial collaborative studies will attempt to correlate the extracellular potassium with the intracellular ATP/ADP ratio in the pericruciate cortex.